Biomedical Engineering Reference
In-Depth Information
Class III antiarrhythmics block K
v
channels in the heart (K
v
1, K
v
4, and K
v
11 subtypes) leading
to a prolonged cardiac AP and termination of so-called reentry arrhythmia. Dofetilide, d-sotalol
and other antiarrhythmics are selective for the K
v
11 channels (hERG channels). These drugs show
antiarrhythmic effects in some patients whereas they are proarrhythmic in others. The reason for
the latter is that although the prolongation of the AP may terminate some arrhythmias, then block-
ing an important cardiac K
+
conductance being responsible for repolarizing the AP may destabilize
the heart against triggered impulses (after depolarizations).
The K
v
11 channel has a high-afi nity binding site in the pore, which interacts with drugs of very
different classes including antihistamines, antipsychotics, antidepressants, antibiotics, and many
more. Proarrhythmia caused by drug binding to this site and channel block has been a major reason
for withdrawal of drugs from the market and discontinued drug development projects, so the K
v
11
channel has become a major cardiac safety pharmacology issue. The Ca-activated K
+
channels, K
Ca
,
are divided into three families depending on their single-channel conductance. They are gated by
Ca
2+
binding either directly to the channel or indirectly to a constitutively bound calmodulin. The
channels are generally involved in attenuating the activity of a given cell by hyperpolarizing this,
when the internal Ca
2+
concentration rises.
TRP belong structurally to this group having six TM, a voltage sensor in S4, and a pore loop
between S5 and S6. Despite the structural similarity to K
v
channels the 28 different TRP subtypes
can be either selective to Na
+
/K
+
, Mg
2+
, or Ca
2+
, and functionally they may associate with G-protein-
coupled receptors, tyrosine kinases, or phospholipase C. A large number of TRP channel subunits
have been cloned and based on their amino acid homology they can be divided into the TRPV-,
TRPC-, and TRPM-families.
Due to their relatively recent discovery, only few TRP-subtype selective ligands have been iden-
tii ed. But there is no doubt that the one TRP channel that has attracted the most attention as a poten-
tial drug target is the TRPV1-channel. This ion channel is activated by heat but also by capsaicin,
a constituent of chili pepper and TRPV1 is indeed responsible for the “hot” sensation induced by
ingesting chili. TRPV1 has also been found to be upregulated in various animal models of chronic
pain and selective antagonists of TRPV1 reduce pain sensation in these models. Selective antago-
nists of TRPV1 are currently undergoing clinical trials in patients suffering from different types of
chronic pain.
13.3
VOLTAGE-GATED CALCIUM CHANNELS
13.3.1 S
TRUCTURE
AND
M
OLECULAR
B
IOLOGY
The discovery of voltage-gated calcium channels (Ca
v
) was originally made in the 1950s, through an
investigation of crab leg muscle contraction. These experiments revealed that both membrane depo-
larization and muscle contraction depend on extracellular calcium ions, inferring that the muscle
cells posses some membrane molecules enabling calcium to selectively permeate. By use of electro-
physiological techniques, it was later found that a variety of functionally distinct Ca
v
s exist and that
these ion channels are also expressed in nerve cells.
Functionally, Ca
v
s are closed at the resting membrane potential (i.e., −50 to −80 mV), but are
activated by depolarization. Two distinct classes of Ca
v
-mediated currents can be distinguished
by this feature: high-voltage-activated calcium currents, requiring membrane potentials of ca.
−20 to +10 mV to activate and low-voltage activated currents, which activate at much more negative
membrane potentials, typically −50 to −40 mV. Following activation, Ca
v
s inactivate in the presence
of sustained membrane depolarization, although the speed of inactivation can vary from ~50 ms to
several seconds. Therefore, different types of Ca
v
s can be distinguished on the basis of biophysical, i.e.,
activation and inactivation characteristics, and on pharmacological properties. Voltage-activated
calcium currents, measured in native tissues, have traditionally been classii ed as L-, N-, P/Q-, or
R-type or T-type currents (see Table 13.2).
